PLX053931

GSE142357: Selective inhibition of HDAC3 targets synthetic vulnerabilities and activates immune surveillance in lymphoma

• Organsim human
• Type RNASEQ
• Target gene
• Project ARCHS4

CREBBP mutations are highly recurrent in B-cell lymphomas and either inactivate its histone acetyltransferase (HAT) domain or truncate the protein. Herein, we show that these two classes of mutations yield different degrees of disruption of the epigenome, with HAT mutations being more severe and associated with inferior clinical outcome. Genes perturbed by CREBBP mutation are direct targets of the BCL6/HDAC3 onco-repressor complex. Accordingly, we show that HDAC3 selective inhibitors reverse CREBBP mutant aberrant epigenetic programming resulting in: a) growth inhibition of lymphoma cells through induction of BCL6 target genes such as CDKN1A and b) restoration of immune surveillance due to induction of BCL6-repressed IFN pathway and antigen presentation genes. By reactivating these genes, exposure to HDAC3-i restored the ability of tumor infiltrating lymphocytes to kill DLBCL cells in an MHC II and MHC I dependent manner, and synergized with PD-L1 blockade in a syngeneic model in vivo. Hence HDAC3-i represents a novel mechanism-based immune-epigenetic therapy for CREBBP mutant lymphomas. SOURCE: Matt Teater (mrt2001@med.cornell.edu) - Weill Cornell Medical College